Insulin Inhibition of beta-AR Signaling in the Myocardium

 描述（由申请人提供）：肥胖、2型糖尿病（T2 DM）和胰岛素抵抗是心力衰竭的独立风险因素。本提案的长期目标是了解这些人群中高胰岛素血症和心功能不全之间的关系。高胰岛素血症也可能加速压力超负荷肥大中的不利LV重构，并且心肌细胞中胰岛素信号传导的遗传减少限制了肥大重构并减少了压力超负荷中的细胞凋亡，从而保护了LV功能。我们最近的研究表明，高胰岛素血症通过促进β 2ARG 1-偏置信号传导和诱导磷酸二酯酶（PDE 4D）使β 2ARG 1-介导的心脏收缩性刺激脱敏，这代表了连接胰岛素抵抗、高胰岛素血症和LV功能障碍的新机制。该提议将检验高胰岛素血症通过两种不同机制直接损害α 2 AR信号传导来减弱LV收缩性的假设：（1）增加α 2 AR/Gi偶联，其抑制腺苷酸环化酶（AC）和cAMP产生，和（2）增加PDE 4D的表达，其增加cAMP降解。该多PI提案反映了Evan Dale Abel（爱荷华州大学）和Yang Kevin Xiang（加州-戴维斯大学）实验室的积极合作。我们在心肌胰岛素信号传导和心肌肾上腺素能信号传导方面的综合专业知识，使用新型分子生物传感器来定义心肌细胞中的亚细胞肾上腺素能信号传导结构域，以及一系列具有干扰IR或βAR信号传导的突变小鼠模型，将在以下三个具体目标中解决这一假设。目的1（Xiang）：将确定慢性高胰岛素血症诱导PDE 4的分子机制和结果。假设：胰岛素信号通过增加心脏PDE 4水平来降低cAMP水平，从而通过PDE 4转录和蛋白质周转的β 2 AR-ERK依赖性调节来水解cAMP。目的2（Abel）：将确定IR-β 2AR信号转导的调节可以减轻肥胖相关的LV功能障碍的机制。假设：急性或慢性高胰岛素血症将损害心肌βAR信号传导，并通过促进cAMP降解降低收缩力或正性肌力储备，这种串扰的遗传或药理学抑制将在高胰岛素血症状态下保护LV功能。目标3（阿贝尔）。将确定IR-受体2AR串扰是否导致心力衰竭或胰岛素抵抗受试者的LV功能障碍。假设：来自患有心力衰竭的受试者的LV或心房组织将显示与增加的IR-β 2 AR ERK激活和PDE 4诱导一致的分子特征，并且胰岛素抗性受试者将表现出对次最大运动的心率反应受损。这些研究将全面剖析在胰岛素抵抗状态下限制心肌收缩力的IR-β-AR串扰的机制，并可能导致治疗或预防具有胰岛素抵抗和代谢综合征的高危人群中的心力衰竭的新方法。

 DESCRIPTION (provided by applicant): Obesity, type 2 diabetes (T2DM), and insulin resistance are independent risk factors for heart failure. The long- term goal of this proposal is to understand the relationship between hyperinsulinemia and cardiac dysfunction in these populations. Hyperinsulinemia may also accelerate adverse LV remodeling in pressure overload hypertrophy and genetic reduction of insulin signaling in cardiomyocytes limits hypertrophic remodeling and reduces apoptosis in pressure overload, thereby preserving LV function. Our recent studies reveal that hyperinsulinemia desensitizes ß-AR-mediated stimulation of cardiac contractility by promoting ß2ARGi-biased signaling and by inducing the phosphodiesterase (PDE4D), which represents a novel mechanism linking insulin resistance, hyperinsulinemia and LV dysfunction. This proposal will test the hypothesis that hyperinsulinemia attenuates LV contractility by directly impairing AR signaling via two distinct mechanisms: (1) Increased 2AR/Gi coupling that inhibits adenylyl cyclase (AC) and cAMP production, and (2) Increased expression of PDE4D that increases cAMP degradation. This multi PI proposal reflects an active collaboration by the laboratories of Evan Dale Abel (University of Iowa) and Yang Kevin Xiang (University of California -Davis). Our combined expertise in myocardial insulin signaling and myocardial adrenergic signaling, using novel molecular biosensors to define subcellular adrenergic signaling domains in cardiomyocytes and a comprehensive array of mutant mouse models with perturbed IR or βAR signaling, will address this hypothesis in the following three specific aims. Aim 1 (Xiang): Will define the molecular mechanisms for and consequences of PDE4 induction in response to chronic hyperinsulinemia. Hypothesis: Insulin signaling reduces cAMP levels by increasing cardiac PDE4 levels for cAMP hydrolysis via 2AR-ERK dependent modulation of PDE4 transcription and protein turnover. Aim 2 (Abel): Will determine the mechanisms by which modulation of IR-2AR signaling may attenuate obesity associated LV dysfunction. Hypothesis: Acute or chronic hyperinsulinemia will impair myocardial βAR signaling and reduce contractility or inotropic reserve by promoting cAMP degradation and genetic or pharmacological inhibition of this crosstalk will preserve LV function in hyperinsulinemic states. Aim 3 (Abel). Will determine if IR-2AR crosstalk contributes to LV dysfunction in heart failue or in subjects with insulin resistance. Hypothesis: LV or atrial tissue from subjects with heart failure will reveal molecular signatures consistent with increased IR-2AR ERK activation and PDE4 induction, and insulin resistant subjects will exhibit impaired heart rate responses to sub-maximal exercise. These studies will comprehensively dissect the mechanism for IR-AR crosstalk that limits myocardial contractility in insulin resistant states, and may lead to novel approaches for treating or preventing heart failure in the high risk population with insulin resistance and the metabolic syndrome.